Cardiovascular disease as result of metabolic syndrome continues to be a major health burden worldwide, regardless of the numerous available therapeutic strategies. Derangements in systemic energy homeostasis are the result of metabolic dysfunction within individual tissues as well as in defective communication between tissues. Understanding metabolic coordination within a particular tissue and throughout the body will lead to new and improved therapeutic avenues. We recently uncovered an important role of the heart in systemic energy homeostasis, thus establishing the precedent that the heart is capable of intertissue metabolic communication to elicit fuel partitioning between tissues globally. However, the molecular details of the signals emanating from the heart and the role of this cardiometabolic axis in disease are unexplored. We have identified 2 uncharacterized muscle-specific lipid reductase enzymes capable of generating metabolites that could confer the heart this ability. In the first aim of this proposal, we will interrogate the functions of each of these enzymes in cardiomyocytes using gain- and loss-of-function animal models. The final aim of this proposal will test the role of each lipid reductase in mediating inter-tissue communication from myocytes to other tissues of the body. The overall goal of this proposal is to test the hypothesis that the heart signals to other tissues by secreting lipid-derived metabolites that act as signaling effectors, with the prediction that we will uncover novel ways in which striated muscles communicate to other tissues. Overall, these studies will provide new insights into myocyte endocrine signaling and the regulation of systemic energy metabolism by striated muscle and may yield novel therapeutic strategies for modulating these processes in the settings of cardiometabolic disease.